Pyridone, pyridazone and triazone derivatives as lp-pla2 inhibitors

ABSTRACT

Compounds of the formula (I) are inhibitors of the enzyme Lp-PLA2 and are of use in therapy, in particular for treating atherosclerosis.

The present invention relates to certain novel pyridone, pyridazone andtriazinone compounds, processes for their preparation, intermediatesuseful in their preparation, pharmaceutical compositions containing themand their use in therapy, in particular in the treatment ofatherosclerosis.

WO 95/00649 (SmithKline Beecham plc) describes the phospholipase A₂enzyme Lipoprotein Associated Phospholipase A₂ (Lp-PLA₂), the sequence,isolation and purification thereof, isolated nucleic acids encoding theenzyme, and recombinant host cells transformed with DNA encoding theenzyme. Suggested therapeutic uses for inhibitors of the enzyme includedatherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardialinfarction, reperfusion injury and acute and chronic inflammation. Asubsequent publication from the same group further describes this enzyme(Tew D et al, Arterioscler Thromb Vas Biol 1996:16;591-9) wherein it isreferred to as LDL-PLA₂. A later patent application (WO 95/09921, IcosCorporation) and a related publication in Nature (Tjoelker et al, vol374, 6 Apr. 1995, 549) describe the enzyme PAF-AH which has essentiallythe same sequence as Lp-PLA₂ and suggest that it may have potential as atherapeutic protein for regulating pathological inflammatory events.

It has been shown that Lp-PLA₂ is responsible for the conversion ofphosphatidylcholine to lysophosphatidylcholine, during the conversion oflow density lipoprotein (LDL) to its oxidised form. The enzyme is knownto hydrolyse the sn-2 ester of the oxidised phosphatidylcholine to givelysophosphatidylcholine and an oxidatively modified fatty acid. Bothproducts of Lp-PLA₂ action are biologically active withlysophosphatidylcholine in particular having several pro-atherogenicactivities ascribed to it, including monocyte chemotaxis and inductionof endothelial dysfunction, both of which facilitate monocyte-derivedmacrophage accumulation within the artery wall. Inhibition of theLp-PLA₂ enzyme would therefore be expected to stop the build up of thesemacrophage enriched lesions (by inhibition of the formation oflysophosphatidylcholine and oxidised free fatty acids) and so be usefulin the treatment of atherosclerosis.

The increased lysophosphatidylcholine content of oxidatively modifiedLDL is also thought to be responsible for the endothelial dysfunctionobserved in patients with atherosclerosis. Inhibitors of Lp-PLA₂ couldtherefore prove beneficial in the treatment of this phenomenon. AnLp-PLA₂ inhibitor could also find utility in other disease states thatexhibit endothelial dysfunction including diabetes, hypertension, anginapectoris and after ischaemia and reperfusion.

In addition, Lp-PLA₂ inhibitors may also have a general application inany disorder that involves activated monocytes, macrophages orlymphocytes, as all of these cell types express Lp-PLA₂. Examples ofsuch disorders include psoriasis.

Furthermore, Lp-PLA₂ inhibitors may also have a general application inany disorder that involves lipid oxidation in conjunction with LpPLA₂activity to produce the two injurious products, lysophosphatidylcholineand oxidatively modified fatty acids. Such conditions include theaforementioned conditions atherosclerosis, diabetes, rheumatoidarthritis, stroke, myocardial infarction, ischaemia, reperfusion injuryand acute and chronic inflammation.

Patent applications WO 96/12963, WO 96/13484, WO96/19451, WO 97/02242,WO97/217675, WO 97/217676, WO 96/41098, and WO 97/41099 (SmithKlineBeecham plc) disclose inter alia various series of4-thionyl/sulfinyl/sulfonyl azetidinone compounds which are inhibitorsof the enzyme Lp-PLA₂. These are irreversible, acylating inhibitors (Tewet al, Biochemistry, 37, 10087, 1998).

A further class of compounds has now been identified which arenon-acylating inhibitors of the enzyme Lp-PLA₂. Thus, WO 99/24420, WO00/10980, WO 00/66566, WO 00/66567 and WO 00/68208 (SmithKline Beechamplc) disclose a class of pyrimidone compounds. We have now found thatthe pyrimidone ring may be replaced by a pyridone, pyridazone ortriazinone ring to give compounds having good activity as inhibitors ofthe enzyme Lp-PLA₂.

Accordingly, the present invention provides a compound of formula (I):

in which:

-   -   R¹ is an aryl group, optionally substituted by 1, 2, 3 or 4        substituents which may be the same or different selected from        C₍₁₋₆₎alkyl, C₍₁₋₆₎alkoxy, C₍₁₋₆₎alkylthio, hydroxy, halogen,        CN, mono to perfluoro-C₍₁₋₄₎alkyl, mono to        perfluoro-C₍₁₋₄₎alkoxyaryl, and arylC₍₁₋₄₎alkyl;    -   when W is C, R² is hydrogen, halogen, C₍₁₋₃₎alkyl, C₍₁₋₃₎alkoxy,        hydroxyC₍₁₋₃₎alkyl, C₍₁₋₃₎alkylthio, C₍₁₋₃₎alkylsulphinyl,        aminoC₍₁₋₃₎alkyl, mono- or di-C₍₁₋₃₎alkylaminoC₍₁₋₃₎alkyl,        C₍₁₋₃₎alkylcarbonylaminoC₍₁₋₃₎alkyl,        C₍₁₋₃₎alkoxyC₍₁₋₃₎alkylcarbonylaminoC₍₁₋₃₎alkyl,        C₍₁₋₃₎alkylsulphonylaminoC₍₁₋₃₎alkyl, C₍₁₋₃₎alkylcarboxy, or        CR⁶R⁷R⁸; or    -   when W is N, R² is hydrogen, C₍₁₋₃₎alkyl, hydroxyC₍₁₋₃₎alkyl,        aminoC₍₁₋₃₎alkyl, mono- or di-C₍₁₋₃₎alkylaminoC₍₁₋₃₎alkyl,        C₍₁₋₃₎alkylcarbonylaminoC₍₁₋₃₎alkyl,        C₍₁₋₃₎alkoxyC₍₁₋₃₎alkylcarbonylaminoC₍₁₋₃₎alkyl,        C₍₁₋₃₎alkylsulphonylaminoC₍₁₋₃₎alkyl, or CR⁶R⁷R⁸;    -   R³ is hydrogen, C₍₁₋₆₎alkyl which may be unsubstituted or        substituted by 1, 2 or 3 substituents selected from hydroxy,        halogen, OR⁹, COR⁹, carboxy, COOR⁹, CONR¹⁰R¹¹, NR¹⁰R¹¹,        NR⁹COR¹², mono- or di-(hydroxyC₍₁₋₆₎alkyl)amino and        N-hydroxyC₍₁₋₆₎alkyl-N—C₍₁₋₆₎alkylamino; or    -   R³ is Het-C₍₀₋₄₎alkyl in which Het is a 5- to 7-membered        heterocyclyl ring comprising and optionally O or S, and in which        N may be substituted by COR⁹, COOR⁹, CONR¹⁰R¹¹, or C₍₁₋₆₎alkyl        optionally substituted by 1, 2 or 3 substituents selected from        hydroxy, halogen, OR⁹, COR⁹, carboxy, COOR⁹, CONR¹⁰R¹¹ or        NR¹⁰R¹¹, for instance, piperidin-4-yl, pyrrolidin-3-yl;    -   R⁴ is an aryl or a heteroaryl ring optionally substituted by 1,        2, 3 or 4 substituents which may be the same or different        selected from C₍₁₋₆₎alkyl, C₍₁₋₆₎alkoxy, C₍₁₋₆₎alkylthio,        arylC₍₁₋₆₎alkoxy, hydroxy, halogen, CN, COR⁹, carboxy, COOR⁹,        NR⁹COR¹², CONR¹⁰R¹¹, SO₂NR¹⁰R¹¹, NR⁹SO₂R¹², NR¹⁰R¹¹, mono to        perfluoro-C₍₁₋₄₎alkyl and mono to perfluoro-C₍₁₋₄₎alkoxy;    -   R⁵ is an aryl or a heteroaryl ring which is further optionally        substituted by 1, 2, 3 or 4 substituents which may be the same        or different selected from C₍₁₋₁₈₎alkyl, C₍₁₋₁₈₎alkoxy,        C₍₁₋₆₎alkylthio, C₍₁₋₆₎alkylsulfonyl, arylC₍₁₋₆₎alkoxy, hydroxy,        halogen, CN, COR⁹, carboxy, COOR⁹, CONR¹⁰R¹¹, NR⁹COR¹²,        SO₂NR¹⁰R¹¹, NR⁹SO₂R¹², NR¹⁰R¹¹, mono to perfluoro-C₍₁₋₄₎alkyl        and mono to perfluoroC₍₁₋₄₎alkoxy, or C₍₅₋₁₀₎alkyl;    -   R⁶ and R⁷ are each hydrogen or C₍₁₋₄₎alkyl, or R⁶ and R⁷        together with the intervening carbon atom form a        C₍₃₋₆₎cycloalkyl ring;    -   R⁸ is an aryl or heteroaryl group, optionally substituted by 1,        2, 3 or 4 substituents which may be the same or different        selected from C₍₁₋₁₈₎alkyl, C₍₁₋₁₈₎alkoxy, C₍₁₋₁₈₎alkylthio,        arylC₍₁₋₁₈₎alkoxy, hydroxy, halogen, CN, COR⁹, carboxy, COOR⁹,        CONR¹⁰R¹¹, NR⁹COR¹², SO₂NR¹⁰R¹¹, NR⁹SO₂R¹², NR¹⁰R¹¹, mono to        perfluoro-C₍₁₋₄₎alkyl and mono to perfluoro-C₍₁₋₄₎alkoxy; or    -   R⁸ is an aryl or heteroaryl group, optionally substituted by 1        substituent selected from CH₂COOH or a salt thereof, CH₂COOR¹³,        CH₂CONR¹⁰R¹¹, CH₂CN, (CH₂)_(m)NR¹⁰R¹¹, (CH₂)_(m)OH and        (CH₂)_(m)OR⁹ where m is an integer from 1 to 3, optionally in        combination with a further substituent selected from        C₍₁₋₁₈₎alkyl, C₍₁₋₁₈₎alkoxy, C₍₁₋₁₈₎alkylthio,        arylC₍₁₋₁₈₎alkoxy, hydroxy, halogen, CN, COR⁹, carboxy, COOR⁹,        CONR¹⁰R¹¹, NR⁹COR¹², SO₂NR¹⁰R¹¹, NR⁹SO₂R¹², NR¹⁰R¹¹, mono to        perfluoro-C₍₁₋₄₎alkyl and mono to perfluoro-C₍₁₋₄₎alkoxy;    -   R⁹ and R¹² are independently hydrogen or C₍₁₋₁₂₎alkyl, for        instance C₍₁₋₄₎alkyl (e.g. methyl or ethyl);    -   R¹⁰ and R¹¹ which may be the same or different is each selected        from hydrogen, or C₍₁₋₁₂₎alkyl, or R¹⁰ and R¹¹ together with the        nitrogen to which they are attached form a 5- to 7 membered ring        optionally containing one or more further heteroatoms selected        from oxygen, nitrogen and sulphur, and optionally substituted by        one or two substituents selected from hydroxy, oxo, C₍₁₋₄₎alkyl,        C₍₁₋₄₎alkylcarboxy, aryl, e.g. phenyl, or aralkyl, e.g benzyl,        for instance morpholine or piperazine;    -   R¹³ is C₍₁₋₄₎alkyl or a pharmaceutically acceptable in vivo        hydrolysable ester group;    -   U is a C₍₂₋₄₎alkylene group optionally substituted by 1, 2 or 3        substituents selected from methyl and ethyl, CH═CH, (CH₂)_(n)S        or (CH₂)_(n)O where n is 1, 2 or 3; and    -   V is CH, and    -   W is N, X is CH and Y is C,    -   W is N, X is N and Y is C,    -   W is C, X is N and Y is N, or    -   W is C, X is CH and Y is N; or    -   V is N, and    -   W is N, X is CH and Y is C,    -   W is N, X is N and Y is C, or    -   W is C, X is N and Y is N;    -   with the proviso that when V is CH, W is C, X is CH and Y is N,        R² is CR⁶R⁷R⁸ as hereinbefore defined.

In one aspect the aryl group R¹ may be phenyl or naphthyl. Preferably,R¹ is phenyl optionally substituted by halogen, C₍₁₋₆₎alkyl,trifluoromethyl, C₍₁₋₆₎alkoxy, preferably, from 1 to 3 fluoro, morepreferably, 4-fluoro or 2,3-difluoro.

In another aspect when W is C or N, R² may be methyl, ethyl, n-propyl,hydroxymethyl, hydroxyethyl, aminoethyl, dimethylaminomethyl,acetylaminoethyl, 2-(methoxyacetamido)ethyl, mesylaminoethyl,methanesulfonamidoethyl, (methoxyacetamido)ethyl,iso-propylcarboxymethyl, pyrimid-5-ylmethyl (optionally substituted by2-methoxy, 2-trifluoromethyl, 2-(4-morpholino) or 2-dimethylamino),2-oxo-pyrimid-5-ylmethyl or 1-methylpyrazol-4-ylmethyl. Preferably, R²is methyl, ethyl or 1-methylpyrazol-4-ylmethyl.

In another aspect when W is C, R² may be chloro, bromo, methoxy,methylthio, methylsulphinyl or ethylcarboxy.

In another aspect R³ may be hydrogen, methyl, 2-(diethylamino)ethyl,2-(piperidin-1-yl)ethyl, 2-(pyrrolidin-1-yl)ethyl,1-methyl-piperidin-4-yl, 1-ethyl-piperidin-4-yl,1-ethyl-pyrrolidin-2-ylmethyl or 1-(2-methoxyethyl)piperidin-4-yl.Preferably R³ is 1-ethyl-piperidin-4-yl or1-(2-methoxyethyl)piperidin-4-yl.

In another aspect R⁴ may be phenyl or pyridyl. Preferably, R⁴ is phenyl.

In another aspect R⁵ may be phenyl optionally substituted by halogen, ortrifluoromethyl, preferably at the 4-position, or ethyl. Preferably, R⁵is phenyl substituted by trifluoromethyl at the 4-position.

Preferably, R⁴ and R⁵ together form a 4-(phenyl)phenyl or a2-(phenyl)pyridinyl substituent in which the remote phenyl ring may beoptionally substituted by halogen or trifluoromethyl, preferably at the4-position.

In another aspect R⁶ and R⁷ are hydrogen.

In another aspect R⁸ when an aryl group may be phenyl or naphthyl.

In another aspect R⁸ when a heteroaryl group may be a 5- or 6-membered,monocyclic heteroaryl group comprising 1 or 2 nitrogen heteroatoms.

Preferably, R⁸ is pyrimidyl optionally substituted by 1 or 2substituents preferably selected from oxo, arylC₍₁₋₄₎alkyl (e.g.benzyl), C₍₁₋₆₎alkyl (e.g. methyl or ethyl), C₍₃₋₆₎cycloalkyl, hydroxy,C₍₁₋₄₎alkoxy (e.g. methoxy), carboxyC₍₁₋₆₎alkyl,C₍₁₋₆₎alkylcarboxyC₍₁₋₆₎alkyl, di-C₍₁₋₆₎alkylamino, and morpholino; orpyrazolyl optionally substituted by C₍₁₋₆₎alkyl (e.g. methyl or ethyl).

Compounds of the invention include:

-   N-(1-Ethylpiperidin-4-yl)-2-(6-(4-fluorobenzylthio)-3-methyl-4-oxo-4H-pyridazin-1-yl)-N-(4-(4-trifluoromethylphenyl)benzyl)acetamide    bitartrate;-   N-(1-(2-methoxyethyl)piperidinyl)-2-(1-ethyl-4-(4-fluorobenzylthio)-6-oxo-1,6-dihydro-pyridazin-3-yl)-N-(4-(4-trifluoromethylphenyl)benzyl)acetamide    bitartrate;-   N-(1-(2-methoxyethyl)piperidinyl)-2-(1-(1-methyl-4-pyrazolylmethyl)-4-(2-(2,3-difluorophenyl)ethyl)-6-oxo-1,6-dihydropyridazin-3-yl)-N-(4-(4-trifluoromethylphenyl)-benzyl)acetamide    bitartrate; and-   N(1-(2-methoxyethyl)piperidinyl)-2-(1-(1-methyl-4-pyrazolylmethyl)-4-(2,3-difluorobenzylthio)-6-oxo-1,6-dihydropyridazin-3-yl)-N-(4-(4-tfluoromethylphenyl)benzyl)acetamide    bitartrate.

It will be appreciated that compounds of the present invention maycomprise one or more chiral centres so that stereoisomers may be formed.The present invention encompasses all stereoisomers of the compounds offormula (I) including geometric isomers and optical isomers (eg.diastereoisomers and enantiomers) whether as individual stereoisomersisolated such as to be substantially free of the other stereoisomers(ie. pure) or as mixtures thereof including racemic modifications. Anindividual stereoisomer isolated such as to be substantially free ofother stereoisomer (ie. pure) will preferably be isolated such that lessthan 10% preferably less than 1% especially less than 0.1% of the otherstereoisomers is present.

Certain compounds of formula (I) may exist in one of several tautomericforms. It will be understood that the present invention encompasses alltautomers of the compounds of formula (I) whether as individualtautomers or as mixtures thereof.

It will be appreciated that in some instances, compounds of the presentinvention may include a basic function such as an amino group as asubstituent. Such basic functions may be used to form acid additionsalts, in particular pharmaceutically acceptable salts. Pharmaceuticallyacceptable salts include those described by Berge, Bighley, andMonkhouse, J. Pharm. Sci., 1977, 66, 1-19. Such salts may be formed frominorganic and organic acids. Representative examples thereof includemaleic, fumaric, benzoic, ascorbic, pamoic, succinic,bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic,propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic,palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, taurocholicacid, benzenesulfonic, p-toluenesulfonic, hydrochloric, hydrobromic,sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.

It will be appreciated that in some instances, compounds of the presentinvention may include a carboxy group as a substituent. Such carboxygroups may be used to form salts, in particular pharmaceuticallyacceptable salts. Pharmaceutically acceptable salts include thosedescribed by Berge, Bighley, and Monkhouse, J. Pharm Sci., 1977, 66,1-19. Preferred salts include alkali metal salts such as the sodium andpotassium salts.

When used herein, the term “alkyl” and similar terms such as “alkoxy”includes all straight chain and branched isomers. Representativeexamples thereof include methyl, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, t-butyl, n-pentyl and n-hexyl.

When used herein, the term “aryl” refers to, unless otherwise defined, amono- or bicyclic aromatic ring system containing up to 10 carbon atomsin the ring system, for instance phenyl or naphthyl.

When used herein, the term “heteroaryl” refers to a mono- or bicyclicheteroaromatic ring system comprising up to four, preferably 1 or 2,heteroatoms each selected from oxygen, nitrogen and sulphur. Each ringmay have from 4 to 7, preferably 5 or 6, ring atoms. A bicyclicheteroaromatic ring system may include a carbocyclic ring.

When used herein, the terms “halogen” and “halo” include fluorine,chlorine, bromine and iodine and fluoro, chloro, bromo and iodo,respectively.

It is to be understood that the present invention covers allcombinations of substituent groups referred to above.

Since the compounds of the present invention, in particular compounds offormula (I), are intended for use in pharmaceutical compositions, itwill be understood that they are each provided in substantially pureform, for example at least 50% pure, more suitably at least 75% pure andpreferably at least 95% pure (% are on a wt/wt basis). Impurepreparations of the compounds of formula (I) may be used for preparingthe more pure forms used in the pharmaceutical compositions. Althoughthe purity of intermediate compounds of the present invention is lesscritical, it will be readily understood that the substantially pure formis preferred as for the compounds of formula (I). Preferably, wheneverpossible, the compounds of the present invention are obtained incrystalline form.

When some of the compounds of this invention are allowed to crystalliseor are re-crystallised from organic solvents, solvent of crystallisationmay be present in the crystalline product. This invention includeswithin its scope such solvates. Similarly, some of the compounds of thisinvention may be crystallised or re-crystallised from solventscontaining water. In such cases water of hydration may be formed. Thisinvention includes within its scope stoichiometric hydrates as well ascompounds containing variable amounts of water that may be produced byprocesses such as lyophilisation. In addition, different crystallisationconditions may lead to the formation of different polymorphic forms ofcrystalline products. This invention includes within its scope allpolymorphic forms of the compounds of formula (I).

Compounds of the present invention are inhibitors of the enzymelipoprotein associated phospholipase A₂ (Lp-PLA₂) and as such areexpected to be of use in therapy, in particular in the treatment ofatherosclerosis. In a further aspect therefore the present inventionprovides a compound of formula (I) for use in therapy.

The compounds of formula (I) are inhibitors of lysophosphatidylcholineproduction by Lp-PLA₂ and may therefore also have a general applicationin any disorder that involves endothelial dysfunction, for exampleatherosclerosis, diabetes, hypertension, angina pectoris and afterischaemia and reperfusion. In addition, compounds of formula (I) mayhave a general application in any disorder that involves lipid oxidationin conjunction with enzyme activity, for example in addition toconditions such as atherosclerosis and diabetes, other conditions suchas rheumatoid arthritis, stroke, inflammatory conditions of the brainsuch as Alzheimer's Disease, myocardial infarction, reperfusion injury,sepsis, and acute and chronic inflammation.

Further applications include any disorder that involves activatedmonocytes, macrophages or lymphocytes, as all of these cell typesexpress Lp-PLA₂. Examples of such disorders include psoriasis.

Accordingly, in a further aspect, the present invention provides for amethod of treating a disease state associated with activity of theenzyme Lp-PLA₂ which method involves treating a patient in need thereofwith a therapeutically effective amount of an inhibitor of the enzyme.The disease state may be associated with the increased involvement ofmonocytes, macrophages or lymphocytes; with the formation oflysophosphatidylcholine and oxidised free fatty acids; with lipidoxidation in conjunction with Lp PLA₂ activity; with ischemia andreperfusion; or with endothelial dysfunction.

Compounds of the present invention may also be of use in treating theabove mentioned disease states in combination with ananti-hyperlipidaemic, anti-atherosclerotic, anti-diabetic, anti-anginal,anti-inflammatory, or anti-hypertension agent or an agent for loweringLp(a). Examples of the above include cholesterol synthesis inhibitorssuch as statins, anti-oxidants such as probucol, insulin sensitisers,calcium channel antagonists, and anti-inflammatory drugs such as NSAIDs.Examples of agents for lowering Lp(a) include the aminophosphonatesdescribed in WO 97/02037, WO 98/28310, WO 98/28311 and WO 98/28312(Symphar SA and SmnithKline Beecham).

A preferred combination therapy will be the use of a compound of thepresent invention and a statin. The statins are a well known class ofcholesterol lowering agents and include atorvastatin, simvarstatin,pravastatin, cerivastatin, fluvastatin, lovastatin and ZD 4522 (alsoreferred to as S-4522, rosuvastatin, Astra Zeneca). The two agents maybe administered at substantially the same time or at different times,according to the discretion of the physician.

A further preferred combination therapy will be the use of a compound ofthe present invention and an anti-diabetic agent or an insulinsensitiser, as coronary heart disease is a major cause of death fordiabetics. Within this class, preferred compounds for use with acompound of the present invention include the PPARgamma activators, forinstance GI262570 (GlaxoSmithKline) and the glitazone class of compoundssuch as rosiglitazone (Avandia, GlaxoSmithKline), troglitazone andpioglitazone.

In therapeutic use, the compounds of the present invention are usuallyadministered in a standard pharmaceutical composition. The presentinvention therefore provides, in a further aspect, a pharmaceuticalcomposition comprising a compound of formula (I) and a pharmaceuticallyacceptable carrier, optionally with one or more other therapeuticcompounds such as a statin or an anti-diabetic.

Suitable pharmaceutical compositions include those which are adapted fororal or parenteral administration or as a suppository, particularly fororal administration.

Compounds of formula (I) which are active when given orally can beformulated as liquids, for example syrups, suspensions or emulsions,tablets, capsules and lozenges. A liquid formulation will generallyconsist of a suspension or solution of the compound or pharmaceuticallyacceptable salt in a suitable liquid carrier(s) for example, ethanol,glycerine, non-aqueous solvent, for example polyethylene glycol, oils,or water with a suspending agent, preservative, flavouring or colouringagent. A composition in the form of a tablet can be prepared using anysuitable pharmaceutical carrier(s) routinely used for preparing solidformulations. Examples of such carriers include magnesium stearate,starch, lactose, sucrose and cellulose. A composition in the form of acapsule can be prepared using routine encapsulation procedures. Forexample, pellets containing the active ingredient can be prepared usingstandard carriers and then filled into a hard gelatin capsule;alternatively, a dispersion or suspension can be prepared using anysuitable pharmaceutical carrier(s), for example aqueous gums,celluloses, silicates or oils and the dispersion or suspension thenfilled into a soft gelatin capsule. Typical parenteral compositionsconsist of a solution or suspension of the compound of formula (I) in asterile aqueous carrier or parenterally acceptable oil, for examplepolyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil orsesame oil. Alternatively, the solution can be lyophilised and thenreconstituted with a suitable solvent just prior to administration. Atypical suppository formulation comprises a compound of formula (I)which is active when administered in this way, with a binding and/orlubricating agent such as polymeric glycols, gelatins or cocoa butter orother low melting vegetable or synthetic waxes or fats.

Preferably the composition is in unit dose form such as a tablet orcapsule. Each dosage unit for oral administration contains preferablyfrom 1 to 500 mg (and for parenteral administration contains preferablyfrom 0.1 to 25 mg) of a compound of the formula (I). The daily dosageregimen for an adult patient may be, for example, an oral dose ofbetween 1 mg and 1000 mg, preferably between 1 mg and 500 mg, or anintravenous, subcutaneous, or intramuscular dose of between 0.1 mg and100 mg, preferably between 0.1 mg and 25 mg, of the compound of theformula (I), the compound being administered 1 to 4 times per day.Suitably the compounds will be administered for a period of continuoustherapy, for example for a week or more.

According to a first process A, a compound of formula (I) may beprepared by reacting an acid compound of formula (II):

in which U, V, W, X, Y, R¹ and R² are as hereinbefore defined,with an amine compound of formula (III):R⁵—R⁴—CH₂NHR³  (III)in which R³, R⁴ and R⁵ are as hereinbefore defined; under amide formingconditions.

Suitable amide forming conditions are well known in the art and includetreating the acid of formula (II) with the amine of formula (III) in thepresence of a coupling agent such as1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide (DEC) orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) in an aprotic solvent such as dichloromethaneor dimethylformamide (DMF).

A compound of formula (II) may be readily prepared from a correspondingester of formula (IV):

in which V, W, X, Y and R² are as hereinbefore defined, R^(1A) and U^(A)are R¹ and U as hereinbefore defined or a group, or groups, convertibleto R¹ and U, and R¹⁴ is optionally substituted C₍₁₋₆₎alkyl, for examplemethyl, ethyl, t-butyl or 1,1-diphenylmethyl, by treating with ade-esterifying agent, for instance, for t-butyl, trifluoroacetic acid.

The ester of formula (IV) may be readily prepared by adapting standardpyridone, pyridazone and triazinone syntheses. General methods forpreparing pyridones, pyridazones and triazinones are well known in theart and are described in, for example, Comprehensive HeterocyclicChemistry, eds. A. R. Katritzky and C. W. Rees (Pergamon Press, Oxford1984) and Comprehensive Heterocyclic Chemistry II, eds. A. R. Katritzky,C. W. Rees and E. F. V. Scriven (Pergamon Press, Oxford 1996).

For example, for compounds of formula (I) comprising a 6-oxo-1,6dihydropyridazine ring, the ring may be prepared by reaction of acompound of formula (V)

in which R^(1A) and U^(A) are R¹ and U as hereinbefore defined or agroup, or groups, convertible to R¹ and U, and R¹⁴ is1,1-diphenylmethyl,with hydrazine hydrate in ethanol.

For compounds of formula (I) comprising a 4-oxo-4H-pyridazine ring, thering may be prepared by reacting a compound of formula (VI)

with a base such as DMF and a solution of semicarbazide hydrochloride inwater and DMF, and subsequently forming the oxo group by treating withsodium in methanol and then refluxing with concentrated hydrochloricacid.

Conversion of R^(1A) and U^(A) to R¹ and U typically arises if aprotecting group, or a group which can take part in subsequent reactionssuch as coupling reactions, is needed during the above reactions orduring the preparation of the reactants. The conversion of R^(1A) andU^(A) to R¹ and U may be carried out at different stages in thesynthesis of the compounds of formula (I) depending on the nature of R¹and U, including as a final step.

R^(1A) and U^(A) may, for example, be a single group such as halo, forexample chloro, bromo or iodo, which can be converted to give R¹ and Uusing one of the general methods for functional group transformationdescribed in the literature provided that the method chosen iscompatible with the other functional groups in the molecule. Functionalgroup transformations are well known in the art and are described in forinstance Comprehensive Organic Functional Group Transformations, eds. A.R. Katritzky, O. Meth-Cohn and C. W. Rees (Elsevier Science Ltd.,Oxford, 1995), Comprehensive Organic Chemistry, eds. D. Barton and W. D.Ollis (Pergamon Press, Oxford, 1979), and Comprehensive OrganicTransformations, R. C. Larock (VCH Publishers Inc., New York, 1989).

Thus, according to a further process B, compounds of formula (I) may beprepared by converting a compound of formula (VII):

in which R^(1A), U^(A), V, W, Y, R², R³, R⁴ and R⁵ are as defined, to acompound to formula (I) by deprotection or functional grouptransformation.

The present invention will now be illustrated by the following examples.

EXAMPLES

The structure and purity of the intermediates and examples was confirmedby 1H-NMR and (in nearly all cases) mass spectroscopy, even where notexplicitly indicated below.Intermediate A1—5,5,5-Trichloro-pent-3-ene-2-one

To a solution of diethyl(2-oxopropyl)phosphonate (20 g) in drydimethylformamide (DMF) (400 ml) was cooled to 5° C. under argon. Sodiumhydride (60% in oil, 4.53 g) was added portionwise over 1 h whilstmaintaining the temperature between 5-8° C. The pale orange solution wasstirred in an ice-bath and chloral (11.04 ml) in dry dimethoxyethane(200 ml) added over 1 h whilst keeping the temperature <8° C. Afterstirring in an ice bath for a further 30 min, the mixture was pouredinto water and extracted with diethyl ether (×3). The organic layerswere combined, washed with brine, dried over MgSO₄ and evaporated underreduced pressure. The dark brown oil so formed was chromatographed onsilica gel eluting with 9:1 hexane:ethyl acetate to give the titlecompound. ¹H NMR (CDCl₃) δ 2.38 (3H, s), 6.6 (1H, d), 7.04 (1H, d).Intermediate A2—3,5,5,5-Tetrachloro-pent-3-ene-2-one

A solution of intermediate A1 (12.5 g) in carbon tetrachloride (75 ml)was cooled to 3° C. under argon. Iodine (1.2 g) was added followed by asolution of chlorine (4.15 g) in carbon tetrachloride (50 ml) over 1 hkeeping the temperature below 5° C. The mixture was stirred in an icebath for 30 min and washed with 10% aq sodium sulphite (75 ml). Theaqueous layer was extracted with dichloromethane, the organic layerscombined and washed with brine. This solution was dried over MgSO₄ andevaporated under reduced pressure to an oil that was dissolved inglacial acetic acid (40 ml) and anhydrous sodium acetate (5.47 g) added.The suspension was heated at 80° C. under argon for 2.5 h, cooled andevaporated under reduced pressure. The residue was partitioned betweendiethyl ether and water. The aqueous layer was washed with furtherdiethyl ether and the combined organic layers washed with dilute brine,dried over MgSO₄ and evaporated under reduced pressure to a dark oilthat was purified by chromatography on silica gel eluting with hexane.This gave the title compound (5.8 g). ¹H NMR (CDCl₃) δ 2.52 (3H, s),7.56 (1H, s).Intermediate A3—4,6-Dichloro-3-methylpyridazine.

A solution of intermediate A2 (5.8 g) in DMP (30 ml) was cooled in anice-bath and a solution of semicarbazide hydrochloride (2.93 g) in water(4.1 ml)/DMF (11.1 ml) added over 30 min. The cooling bath was removed,the mixture stirred at room temperature for 3 h and reduced to halfvolume under reduced pressure. Water was added, the mixture extractedwith diethyl ether (×3), the combined organic layers washed with brineand dried over MgSO₄. The solvent was removed under reduced pressure andpurified by chromatography on silica gel using hexane:ethyl acetate aseluent. This gave the title compound as a waxy solid (2.75 g). ¹H NMR(CDCl₃) δ 2.78 (3H, s), 7.54 (1H, s).Intermediate A4—6-Chloro-4-methoxy-3-methylpyridazine.

A solution of intermediate A3 (2.6 g) in dry tetrahydrofuran (45 ml) wascooled to 5° C. and a solution of sodium (0.405 g) in methanol (8.6 ml)added over 20 min. After a further 20 min in an ice bath and 15 min atroom temperature, the mixture was evaporated to dryness and partitionedbetween water and ethyl acetate. The aqueous layer was washed withfurther ethyl acetate and the combined organic layers washed with brine,dried over MgSO₄ and evaporated under reduced pressure. The residue wastriturated with diethyl ether/hexane and the light brown title compound(1.69 g) collected by filtration. ¹H NMR (CDCl₃) δ 2.56 (3H, s), 3.92(3H, s), 6.81 (1H, s).Intermediate A5—6-(4-Fluorobenzylthio)-4-methoxy-3-methylpyridazine.

A solution of 4-fluorobenzylmercaptan (1.7 g) in dry tetrahydrofuran(THF) was added to a suspension of sodium hydride (60% in oil, 0.5 g) indry THF (20 ml) over 15 min under argon. After 15 min at roomtemperature, a solution of intermediate A4 (1.6 g) in dry THF (20 ml)was added and the mixture was heated to reflux for 2 h. After cooling,the mixture was partitioned between ethyl acetate and dilute brine. Theaqueous layer was extracted with further ethyl acetate and the combinedorganic layers were dried over MgSO₄ and evaporated under reducedpressure to give an oil that was chromatographed on silica gel usinghexane:ethyl acetate as eluents. This gave the title compound (2.39 g).¹H NMR (CDCl₃) δ 2.51 (3H, s), 3.83 (3H, s), 4.55 (2H, s), 6.56 (1H, s),6.9-7.05 (2H, m), 7.35-7.5 (2H, m).Intermediate A6—6-(4-Fluorobenzylthio)-3-methyl-1H-pyridazin-4-one.

A mixture of intermediate A5 and conc.hydrochloric acid (20 ml) wasstirred at reflux for 44 h. After cooling, the suspension was filteredand washed well with water and diethyl ether. The residue was suspendedin saturated sodium bicarbonate, stirred well and filtered. The solidwas washed with water and dried to give the title compound (1.8 g). Thecombined aqueous filtrates were washed with dichloromethane and theorganic layer washed with dilute brine and dried over MgSO₄. Thesolution was evaporated under reduced pressure and triturated withdiethyl ether to give further title compound (0.35 g). ¹H NMR (d₆-DMSO)δ 2.50 (3H, s), 4.37 (2H, s), 6.32 (1H, br s), 7.05-7.25 (2H, m),7.35-7.5 (2H, m).IntermediateA7—Ethyl(6-(4-fluorobenzylthio)-3-methyl-4-oxo-pyridazin-1-yl)acetate

Intermediate A6 (0.5 g) was added to a suspension of sodium hydride (60%in oil, 0.088 g) in THF under argon. After a few minutes, DMF (5 ml) wasadded and the suspension stirred for a further 15 min. Ethylbromoacetate (0.244 ml) was added. After a further 30 min further DMF (5ml) was added and the mixture stirred at room temperature for a further21 h. The solvent was removed under reduced pressure and the residuepartitioned between ethyl acetate and brine. The aqueous layer wasextracted with further ethyl acetate and the combined organic layerswere combined, dried over MgSO₄ and evaporated under reduced pressure.The material so formed was chromatographed on silica gel using ethylacetate and ethyl acetate:ethanol as eluents to give the title compound(0.12 g) ¹H NMR (CDCl₃) δ 1.29 (3H, t), 2.27 (3H, s), 4.15 (2H, s), 4.26(2H, q), 4.84 (2H, s), 6.40 (1H, s), 6.95-7.1 (2H, m), 7.2-7.35 (2H, m);MS (APCI+) found (M+1)=337; C₁₆H₁₇FO₃N₂S requires 336.IntermediateA8—(6-(4-fluorobenzylthio)-3-methyl-4-oxo-4H-pyridazin-1-yl)acetic acid.

A solution of intermediate A7 (0.10 g) in dioxan (2 ml) was treated witha solution of sodium hydroxide (0.0119 g) in water (2 ml) and stirred atroom temperature for 1 h. The solvent was removed under reduced pressureand the residue acidified to pH4 with 2M hydrochloric acid. Theprecipitate was collected, washed wit water and dried to give the titlecompound (0.39 g). ¹H NMR (d₆-DMSO) δ 2.09 (3H, s), 4.40 (2H, s), 4.89(2H, s), 6.41 (1H, s), 7.05-7.25 (2H, m), 7.35-7.5 (2H, m).IntermediateB1—1,1-Diphenylmethyl(3-bromo-5-oxo-5H-furan-2-ylidene)acetate.

To a suspension of1,1-Diphenylmethyl(3-bromo-5-oxo-5H-furan-2-ylidene)acetic acid (4.0 g)(see J. Org. Chem. 1994, 59(14), 4001-4003 and Tetrahedron Lett. 1988,29(48), 6203-6206) in dichloromethane (100 ml) was addeddiphenyldiazomethane (4.26 g) portionwise. After stirring at roomtemperature for 18 h, the solution was concentrated to 25% volume andchromatographed on silica gel using dichloromethane:hexane as eluents.This gave the title compound (4.14 g). ¹H NMR (CDCl₃) δ 5.87 (1H, s),6.64 (1H, s), 7.01 (1H, s), 7.2-7.5 (10H, m).IntermediateB2—1,1-Diphenylmethyl(4-bromo-6-oxo-1,6-dihydropyridazin-3-yl)acetate

To a suspension of intermediate B1 (4.06 g) in ethanol (40 ml) at roomtemperature was added hydrazine hydrate (0.51 ml). After 10 min themixture was heated to reflux for 18 h, cooled and the solid so formedfiltered and washed with ethanol and diethyl ether to give the titlecompound (3.63 g). ¹HNMR (CDCl₃) δ 3.92 (2H, s), 6.94 (1H, s), 7.2-7.4(11H, m), 11.15 (1H, br s).IntermediateB3—1,1-Diphenylmethyl(4-bromo-1-ethyl-6-oxo-1,6-dihydropyridazin-3-yl)acetate.

A mixture of intermediate B2 (0.2 g) in dry DMF at 40° C. was treatedwith sodium hydride (0.022 g) under argon. After 10 min ethyl iodide(0.044 ml) was added and stirred at room temperature. After 2 h, thesolvent was removed under reduced pressure and the residue partitionedbetween dichloromethane and saturated sodium metabisulphite. The organiclayer was washed with brine, dried over MgSO₄ and evaporated underreduced pressure. The residue was chromatographed on silica gel elutingwith dichloromethane:hexane. This gave the title compound (0.181 g). ¹HNMR (CDCl₃) δ 1.31 (3H, t), 3.91 (2H, s), 4.12 (2H, q), 6.94 (1H, s),7.15-7.4 (11H, m).IntermediateB4—Methyl(1-ethyl-4-(4-fluorobenzylthio)-6-oxo-1,6-dihydropyridazin-3-yl)acetate

A solution of intermediate B3 (0.079 g) in methanol was added to asolution of sodium 4-fluorobenzylthiolate (from sodium (0.0043 g) inmethanol (1 ml). After 15 min the solvent was removed under reducepressure and the residue chromatographed on silica gel usingdichloromethane:hexane as eluents. This gave the title compoundcontaminated with its biphenylmethyl ester (0.14 g). ¹HNMR (CDCl₃) δ 1.3(3H, t), 3.68 (2H, s), 3.73 (3H, s), 4.0-4.2 (4H, m), 6.60 (1H, s),6.95-7.1 (2H, m), 7.2-7.35 (2H, m); MS (APCI+) found (M+1)=337;C₁₆H₁₇FN₂O₃S requires 336.

Similarly prepared was:IntermediateB11—1,1-Diphenylmethyl(1-(1-methylpyrazol-4-ylmethyl)-4-(4-fluorobenzylthio)-6-oxo-1,6-dihydropyridazin-3-yl)acetateandMethyl(1-(1-methylpyrazol-4-ylmethyl)-4-(4-fluorobenzylthio)-6-oxo-1,6-dihydropyridazin-3-yl)acetate

From intermediate B8 and 2,3-difluorobenzylthiol.IntermediateB5—(1-Ethyl-4-(4-fluorobenzylthio)-6-oxo-1,6-dihydropyridazin-3-yl)aceticacid

To the mixture of esters containing B4 above (0.252 g) in methanol (3ml) was added a solution of sodium hydroxide (0.5M, 1.03 ml) and thesuspension stirred for 24 h. The mixture was heated to reflux for 10 minand 2 drops of sodium hydroxide (0.5M) added. After heating at refluxfor a further 15 min, the mixture was cooled, acidified with dilutehydrochloric acid and the solvent removed under reduced pressure. Theresidue was partitioned between dichloromethane and water and theorganic layer washed with brine and dried over MgSO₄. Removal of thesolvent under reduced pressure and trituration of the product withdiethyl ether gave the title compound (0.118 g). ¹HNMR (CDCl₃) δ 1.33(3H, t), 3.70 (2H, s), 4.054.2 (4H, m), 6.86 (1H, s), 6.9-7.1 (2H, m),7.25-7.4 (2H, m).

Similarly prepared wasIntermediateB12—(1-(1-Methylpyrazol-4-ylmethyl)-4-(4-fluorobenzylthio)-6-oxo-1,6-dihydropyridazin-3-yl)aceticacid

From intermediate B 11.Intermediate B6—2,3-Difluorophenylacetylene

Trimethylsilylacetylene (4.38 ml) was added to a mixture of1-bromo-2,3-difluorobenzene (4.99 g), copper(I) iodide (0.493 g),tetrakistriphenylphosphine palladium (1.49 g) and triethylamine (20 ml)under argon. The mixture was stirred and heated to reflux for 18 h. Thesolvent was removed under reduced pressure and the residue taken up inethyl acetate and filtered through Celite. The filtrate was washed withsaturated ammonium chloride and brine, dried over MgSO₄ and carefullyevaporated under reduced pressure. Methanol was added and the mixturewas carefully evaporated once more. The material so formed was dissolvedin methanol (10 ml) and added to a solution of potassium hydroxide (14.5g) in methanol (30 ml) with stirring. After 18 h, the solution wasdiluted with water and extracted with diethyl ether. The combineddiethyl ether layers were dried over MgSO₄ and carefully evaporated anddistilled (b.p. 65-115° C./33 mm Hg) to give the title compound. ¹H NMR(CDCl₃) δ 6.99-7.44 (all protons).Intermediate B7—4-Bromomethyl-1-methylpyrazole hydrobromide

To a suspension of 4-formyl-1-methylpyrazole (6 g) in THF (30 ml) at 0°C. under argon was added lithium aluminium hydride (1M in TBF, 27.2 ml)dropwise. The mixture was allowed to warm to room temperature andstirred for 1.5 h. Water (1 ml), 10% sodium hydroxide (1 ml) and water(3 ml) were added sequentially with care, the mixture stirred for afurther 30 min and evaporated under reduced pressure. The residue waspartitioned between dichloromethane and brine, dried over MgSO₄ andevaporated under reduced pressure to give an oil (3.48 g). A portion ofthis material (1.15 g) in acetic acid (5 ml) was mixed with 48% hydrogenbromide in acetic acid and the mixture heated to reflux for 5 h. Thesolvent was removed under reduced pressure and the residue crystallisedfrom dichloromethane and diethyl ether to give the title compound (1.6g) ¹H NMR (D20) δ 4.09 (3H, s), 4.60 (2H, s), 8.07 (2H, s).IntermediateB8-1,1-Diphenylmethyl(4-bromo-1-(1-methylpyrazol-4-ylmethyl)-6-oxo-1,6-dihydropyridazin-3-yl)acetate

To a solution of intermediate B2 (0.5 g) in dry DMF (10 ml) was addedsodium hydride (60% in oil, 0.05 g) at room temperature with stirring,under argon. The mixture was stirred at room temperature for 20 min andintermediate B7 (0.32 g) in dry DMF (3 ml) added followed by furthersodium hydride (60% in oil, 0.055 g). The mixture was stirred at roomtemperature for 4.5 h and evaporated under reduced pressure. The residuewas partitioned between dichloromethane and water and the organic layerwashed with brine and dried over MgSO₄. Removal of the solvent underreduced pressure followed by chromatography on silica gel using ethylacetate:dichloromethane as eluents gave the title compound (0.24 g). ¹HNMR (CDCl₃) δ 3.81 (3H, s), 3.91 (21, s), 5.07 (2H, s), 6.94 (1H, s),7.19 (1H, s), 7.2-7.4 (10H, m), 7.42 (1H, s), 7.49 (1H, s).IntermediateB9—1,1-Diphenylmethyl(4-(2,3-difluorophenylethynyl)-1-(1-methylpyrazol-4-ylmethyl)-6-oxo-1,6-dihydropyridazin-3-yl)acetate

To a solution of intermediate B6 (0.2 g) in triethylamine (10 ml) wasadded intermediate B8 (0.44 g), bistriphenylphosphine palladiumdichloride (0.031 g), copper(I) iodide (0.009 g) and dichloromethane (2ml). The mixture was heated at 70° C. for 18 h, evaporated under reducedpressure and chromatographed on silica gel using dichloromethane:ethylacetate as eluents. This gave the title compound (0.44 g). ¹H NMR(CDCl₃) δ 3.83 (3H, s), 3.95 (2H, s), 5.11 (2H, s), 6.85-7.05 (4H, m),7.1-7.35 (111H, m), 7.4-7.6(2H, m); MS (APCI+) found (M+1)=551;C₃₂H₂₄F₂N₄O₃ requires 550.IntermediateB10—(4-(2-(2,3-difluorophenyl)ethyl)-1-(1-methylpyrazol-4-ylmethyl)-6-oxo-1,6-dihydropyridazin-3-yl)aceticacid

Intermediate B9 (0.44 g) was dissolved in DMF (10 ml) and 10% palladiumon charcoal (0.2 g) added carefully. The mixture was hydrogenated atroom temperature and pressure for 18 h, filtered through Celite and thefiltrate evaporated under reduced pressure. The residue was partitionedbetween diethyl ether and 0.5M sodium hydroxide. The organic layer waswashed with further sodium hydroxide and the combined aqueous layerswashed with diethyl ether and acidified to pH1 with hydrochloric acid.The precipitate so formed was extracted with diethyl ether and thecombined extracts dried over MgSO₄ and evaporated to give the titlecompound (0.19 g). ¹H NMR (46-DMSO) δ 2.65-2.8 (2H, m), 2.9-3.0 (2H, m),3.67 (2H, s), 3.77 (3H, s), 5.01 (2H, s), 6.75 (1H, s), 7.1-7.2 (2H, m),7.2-7.35 (1H, m), 7.36 (1H, s), 7.64 (1H, s).

The following amines are known in the literature. No. ReferenceStructure Name C1 WO 01/60805

N-(1-Ethylpiperidin-4-yl)-4-(4-tri- fluoromethyl- phenyl)benzylamine C2WO 01/60805

N-(1-(2-meth- oxyethyl)piperidin-4-yl)-4-(4-tri- fluoromethyl-phenyl)benzylamine

Example 1N-(1-Ethylpiperidin-4-yl)-2-(6-(4-fluorobenzylthio)-3-methyl-4-oxo-4H-pyridazin-1-yl)-N-(4-(4-trifluoromethylphenyl)benzyl)acetamidebitartrate

O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (0.187 g, 0.6 mmol) was added to a mixture ofintermediate A8 (0.114 g), amine C1 (0.09 g) and diisopropylethylamine(0.104 ml) in dimethylformamide (2 ml) and the resultant solutionstirred for 2 h under argon. The solvent was evaporated and the residuediluted with dichloromethane (30 ml) and washed successively withsaturated ammonium chloride, saturated sodium bicarbonate and dilutebrine. The organic layer was dried (K₂CO₃) and the solvent evaporated.The residue was purified by flash chromatography (CH₂Cl₂/MeOH) to givethe free base of the title compound (0.095 g). ¹H NMR (CDCl₃) δ 0.95(3H, m), 1.6-2.1 (6H, m), 2.26+2.29 (3H, 2xs), 2.3-2.5 (2H, q), 2.9-3.1(2H, m), 4.1+4.16 (2H, 2xs), 4.54.7 (3H, m), 4.82+5.09 (2H, 2xs),6.42+6.45 (1H, 2xs), 6.85-7.1 (2H, m), 7.15-7.4 (4H, m), 7.47.55 (2H,m), 7.6-7.8 (4H, m); MS (APCI+) found (M+1)=653; C₃₅H₆F₄N₄O₂S requires652.

The amine (0.09 g) was dissolved in methanol (2 ml) and tartaric acid(0.022 g) added. After sting for 15 min the solvent was evaporated andthe residue triturated from diethyl ether to afford the title compound(0.10 g). ¹H NMR (d₆-DMSO) δ 0.9-1.15 (3H, m), 1.55-1.95 (4H, m),2.09+2.12 (3H, 2xs), 2.2-2.7 (4H, m), 2.95-3.25 (2H, m),3.754.0+4.2-4.35 (1H, 2xbr), 4.11 (2H, s), 4.34+4.31 (2H, 2xs),4.58+4.69 (2H, 2xs), 5.01+5.37 (2H, 2xs), 6.43+6.44 (1H, 2xs), 6.95-7.25(2H, m), 7.25-7.5 (4H, m), 7.5-7.75 (2H, m), 7.75-7.95 (4H, m).

The following examples were prepared by the method of Example 1. ExampleNo. Precursors Structure Name 2 B5, C2

N-(1-(2-methoxyethyl)-pipe- ridin-4-yl)-2-(1-ethyl-4-(4-fluoro-benzylthio)-6-oxo-1,6-di- hydropyridazin-3-yl)-N-(4-(4-tri-fluoromethyl-phe- nyl)benzyl)acetamide bitartrate 3 B10, C2

N-(1-(2-methoxyethyl)-pipe- ridin-4-yl)-2-(1-(1-methyl-4-py-razolylmethyl)-4-(2-(2,3-di- fluorophenyl)ethyl)-6-oxo-1,6-di-hydropyridazin-3-yl)-N-(4-(4-tri- fluoromethylphenyl)-ben- zyl)acetamidebitartrate 4 B12, C2

N-(1-(2-methoxyethyl)-pipe- ridin-4-yl)-2-(1-(1-methyl-4-py-razolylmethyl)-4-(2,3-di- fluorobenzylthio)-6-oxo-1,6-di-hydropyridazin-3-yl)-N-(4-(4-tri- fluoromethylphenyl)-ben- zyl)acetamidebitartrateBiological Data1. Screen for Lp-PLA₂ Inhibition.

Enzyme activity was determined by measuring the rate of turnover of theartificial substrate (A) at 37° C. in 5 mM HEPES(N-2-hydroxyethylpiperazine-N′-2-ethanesulphonic acid) buffer containing150 mM NaCl, pH 7.4.

Assays were performed in 96 well titre plates.

Recombinant Lp-PLA₂ was purified to homogeneity from baculovirusinfected Sf9 cells, using a zinc chelating column, blue sepharoseaffinity chromatography and an anion exchange column. Followingpurification and ultrafiltration, the enzyme was stored at 6 mg/ml at 4°C. Assay plates of compound or vehicle plus buffer were set up usingautomated robotics to a volume of 170 μl. The reaction was initiated bythe addition of 20 μl of 10× substrate (A) to give a final substrateconcentration of 20 μM and 10 μl of diluted enzyme to an approximatefinal 0.1 nM Lp-PLA₂.

The reaction was followed at 405 nm and 37° C. for 20 minutes using aplate reader with automatic mixing. The rate of reaction was measured asthe rate of change of absorbance.

Results

The compounds described in the Examples were tested as described aboveand had IC₅₀ values in the range <0.1 to 100 nM.

1. A compound of formula (I):

in which: R¹ is an aryl group, optionally substituted by 1, 2, 3 or 4substituents which may be the same or different selected from the groupconsisting of C₍₁₋₆₎alkyl, C₍₁₋₆₎alkoxy, C₍₁₋₆₎alkylthio, hydroxy,halogen, CN, mono to perfluoro-C₍₁₋₄₎alkyl, mono toperfluoro-C₍₁₋₄₎alkoxyaryl, and arylC₍₁₋₄₎alkyl; when W is C, R² ishydrogen, halogen, C₍₁₋₆₎alkyl, C₍₁₋₃₎alkoxy, hydroxyC₍₁₋₃₎alkyl,C₍₁₋₃₎alkylthio, C₍₁₋₃₎alkylsulphinyl, aminoC₍₁₋₃₎alkyl, mono- ordi-C₍₁₋₃₎alkylaminoC₍₁₋₃₎alkyl, C₍₁₋₃₎alkylcarbonylaminoC₍₁₋₃₎alkyl,C₍₁₋₃₎alkoxyC₍₁₋₃₎alkylcarbonylaminoC₍₁₋₃₎alkyl,C₍₁₋₃₎alkylsulphonylaminoC₍₁₋₃₎alkyl, C₍₁₋₃₎alkylcarboxy, or CR⁶R⁷R⁸; orwhen W is N, R² is hydrogen, C₍₁₋₃₎alkyl, hydroxyC₍₁₋₃₎alkyl,aminoC₍₁₋₃₎alkyl, mono- or di-C₍₁₋₃₎alkylaminoC₍₁₋₃₎alkyl,C₍₁₋₃₎alkylcarbonylaminoC₍₁₋₃₎alkyl,C₍₁₋₃₎alkoxyC₍₁₋₃₎alkylcarbonylaminoC₍₁₋₃₎alkyl,C₍₁₋₃₎alkylsulphonylaminoC₍₁₋₃₎alkyl, or CR⁶R⁷R⁸; R³ is hydrogen,C₍₁₋₆₎alkyl which may be unsubstituted or substituted by 1, 2 or 3substituents selected from hydroxy, halogen, OR⁹, COR⁹, carboxy, COOR⁹,CONR¹⁰R¹¹, NR¹⁰R¹¹, NR⁹COR¹², mono- or di-(hydroxyC₍₁₋₆₎alkyl)amino andN-hydroxyC₍₁₋₆₎alkyl-N—C₍₁₋₆₎alkylamino; or R³ is Het-C₍₀₋₄₎alkyl inwhich Het is a 5- to 7-membered heterocyclyl ring comprising N andoptionally O or S, and in which N may be substituted by COR⁹, COOR⁹,CONR¹⁰R¹¹, or C₍₁₋₆₎alkyl optionally substituted by 1, 2 or 3substituents selected from hydroxy, halogen, OR⁹, COR⁹, carboxy, COOR⁹,CONR¹⁰R¹¹ or NR¹⁰R¹¹; R⁴ is an aryl or a heteroaryl ring optionallysubstituted by 1, 2, 3 or 4 substituents which may be the same ordifferent selected from the group consisting of C₍₁₋₆₎alkyl,C₍₁₋₆₎alkoxy, C₍₁₋₆₎alkylthio, arylC₍₁₋₆₎alkoxy, hydroxy, halogen, CN,COR⁹, carboxy, COOR⁹, NR⁹COR¹², CONR¹⁰R¹¹, SO₂NR¹⁰R¹¹, NR⁹SO₂R¹²,NR¹⁰R¹¹, mono to perfluoro-C₍₁₋₄₎alkyl and mono toperfluoro-C₍₁₋₄₎alkoxy; R⁵ is an aryl or a heteroaryl ring which isfurther optionally substituted by 1, 2, 3 or 4 substituents which may bethe same or different selected from the group consisting ofC₍₁₋₁₈₎alkyl, C₍₁₋₁₈₎alkoxy, C₍₁₋₆₎alkylthio, C₍₁₋₆₎alkylsulfonyl,arylC₍₁₋₆₎alkoxy, hydroxy, halogen, CN, COR⁹, carboxy, COOR⁹, CONR¹⁰R¹¹,NR⁹COR¹², SO₂NR¹⁰R¹¹, NR⁹SO₂R¹², NR¹⁰R¹¹, mono to perfluoro-C₍₁₋₄₎alkyland mono to perfluoro-C₍₁₋₄₎alkoxy, or C₍₅₋₁₀₎alkyl; R⁶ and R⁷ are eachhydrogen or C₍₁₋₄₎alkyl, or R⁶ and R⁷ together with the interveningcarbon atom form a C₍₃₋₆₎cycloalkyl ring; R⁸ is an aryl or heteroarylgroup, optionally substituted by 1, 2, 3 or 4 substituents which may bethe same or different selected from C₍₁₋₁₈₎alkyl, C₍₁₋₁₈₎alkoxy,C₍₁₋₁₈₎alkylthio, arylC₍₁₋₁₈₎alkoxy, hydroxy, halogen, CN, COR⁹,carboxy, COOR⁹, CONR¹⁰R¹¹, NR⁹COR¹², SO₂NR¹⁰R¹¹, NR⁹SO₂R¹², NR¹⁰R¹¹,mono to perfluoro-C₍₁₋₄₎alkyl and mono to perfluoro-C₍₁₋₄₎alkoxy; or R⁸is an aryl or heteroaryl group, optionally substituted by 1 substituentselected from CH₂COOH or a salt thereof, CH₂COOR¹³, CH₂CONR¹⁰R¹¹, CH₂CN,(CH₂)_(m)NR¹⁰R¹¹, (CH₂)_(m)OH and (CH₂)_(m)OR⁹ where m is an integerfrom 1 to 3, optionally in combination with a further substituentselected from the group consisting of C₍₁₋₁₈₎alkyl, C₍₁₋₁₈₎alkoxy,C₍₁₋₁₈₎alkylthio, arylC₍₁₋₁₈₎alkoxy, hydroxy, halogen, CN, COR⁹,carboxy, COOR⁹, CONR¹⁰R¹¹, NR⁹COR¹², SO₂NR¹⁰R¹¹, NR⁹SO₂R¹², NR¹⁰R¹¹,mono to perfluoro-C₍₁₋₄₎alkyl and mono to perfluoro-C₍₁₋₄₎alkoxy; R⁹ andR¹² are independently hydrogen or C₍₁₋₁₂₎alkyl; R¹⁰ and R¹¹ which may bethe same or different is each selected from hydrogen, or C₍₁₋₁₂₎alkyl,or R¹⁰ and R¹¹ together with the nitrogen to which they are attachedform a 5- to 7 membered ring optionally containing one or more furtherheteroatoms selected from oxygen, nitrogen and sulphur, and optionallysubstituted by one or two substituents selected from hydroxy, oxo,C₍₁₋₄₎alkyl, C₍₁₋₄₎alkylcarboxy, aryl, e.g. phenyl, or aralkyl; R¹³ isC₍₁₋₄₎alkyl or a pharmaceutically acceptable in vivo hydrolysable estergroup; U is a C₍₂₋₄₎alkylene group optionally substituted by 1, 2 or 3substituents selected from methyl and ethyl, CH═CH, (CH₂)_(n)S or(CH₂)_(n)O where n is 1, 2 or 3; and V is CH, and W is N, X is CH and Yis C, W is N, X is N and Y is C, W is C, X is N and Y is N, or W is C, Xis CH and Y is N; or V is N, and W is N, X is CH and Y is C, W is N, Xis N and Y is C, or W is C, X is N and Y is N; and pharmaceuticallyacceptable salts thereof, with the proviso that when V is CH, W is C, Xis CH and Y is N, R² is CR⁶R⁷R⁸ as hereinbefore defined.
 2. A compoundaccording to claim 1 wherein R¹ is phenyl optionally substituted byhalogen, C₍₁₋₆₎ alkyl, trifluoromethyl or C₍₁₋₆₎ alkoxy.
 3. A compoundaccording to claim 1 wherein R³ may be hydrogen, methyl,2-(diethylamino)ethyl, 2-(piperidin-1-yl)ethyl,2-(pyrrolidin-1-yl)ethyl, 1-methyl-piperidin-4-yl,1-ethyl-piperidin-4-yl, 1-ethylpyrrolidin-2-ylmethyl or1-(2-methoxyethyl)piperidin-4-yl.
 4. A compound according to claim 1wherein R⁴ is phenyl or pyridyl.
 5. A compound according to claim 1wherein R⁵ is phenyl optionally substituted by halogen ortrifluoromethyl.
 6. A compound according to claim 1 wherein W is C or Nand R² is methyl, ethyl, n-propyl, hydroxymethyl, hydroxyethyl,aminoethyl, dimethylaminomethyl, acetylaminoethyl,2-(methoxyacetamido)ethyl, mesylaminoethyl, methanesulfonamidoethyl,(methoxyacetamido)ethyl, iso-propylcarboxymethyl, pyrimid-5-ylmethyl(optionally substituted by 2-methoxy, 2-trifluoromethyl,2-(4-morpholino) or 2-dimethylamino), 2-oxo-pyrimid-5-ylmethyl or1-methylpyrazol-4-ylmethyl.
 7. A compound according to claim 1 which isN-(1-Ethylpiperidin-4-yl)-2-(6-(4-fluorobenzylthio)-3-methyl-4-oxo-4H-pyridazin-1-yl)-N-(4-(4-trifluoromethylphenyl)benzyl)acetamidebitartrate;N-(1-(2-methoxyethyl)piperidin-4-yl)-2-(1-ethyl-4-(4-fluorobenzylthio)-6-oxo-1,6-dihydropyridazin-3-yl)-N-(4-(4-trifluoromethylphenyl)benzyl)acetamidebitartrate;N-(1-(2-methoxyethyl)piperidin-4-yl)-2-(1-(1-methyl-4-pyrazolylmethyl)-4-(2-(2,3-difluorophenyl)ethyl)-6-oxo-1,6-dihydropyridazin-3-yl)-N-(4-(4-trifluoromethylphenyl)benzyl)acetamidebitartrate; andN-(1-(2-methoxyethyl)piperidin-4-yl)-2-(1-(1-methyl-4-pyrazolylmethyl)-4-(2,3-difluorobenzylthio)-6-oxo-1,6-dihydropyridazin-3-yl)-N-(4-(4-trifluoromethylphenyl)benzyl)acetamidebitartrate.
 8. A pharmaceutical composition comprising a compound offormula (I) as claimed in claim 1 and a pharmaceutically acceptablecarrier.
 9. A compound of formula (I) as claimed in claim 1 for usetreating atherosclerosis.
 10. (Deleted)
 11. A method of treating adisease state associated with activity of the enzyme Lp-PLA₂ whichmethod involves treating a patient in need thereof with atherapeutically effective amount of a compound of formula (I) as claimedin claim
 1. 12. A process for preparing a compound of formula (I) asdefined in claim 1 which process comprises reacting an acid compound offormula (II):

in which U, V, W, X, Y, R¹ and R² are as hereinbefore defined, with anamine compound of formula (III):R⁵—R⁴—CH₂NHR³  (III) in which R³, R⁴ and R⁵ are as hereinbefore defined;under amide forming conditions.